1. Field of the Invention
The present invention relates to hormone. replacement therapy (HRT) for administration to menopausal or castrate women. More specifically, the present invention relates to a hormone replacement therapy regimen comprising a specific dosage combination that includes a reduced amount of estrogen, which provides a reduced risk of cancer, while providing a regimen with vasomotor symptom relief that is usually only available at higher estrogen levels.
1. Background Art
There are a number of patents relating to hormone replacement therapy and many different formulations available in the marketplace. Many formulations involve the administration of continuous estrogen and progestogen, while other regimens can be characterized as interrupted or cyclophasic. Examples of patents covering interrupted regimens include Robert F. Casper's U.S. Pat. No. 5,108,995 issued Aug. 28, 1992, for a method of HRT; U.S. Pat. No. 5,256,421 issued Oct. 26, 1993 for an HRT method; U.S. Pat. No. 5,422,119 issued Jun. 6, 1995 for a transdermal HRT method, preparation and package; and U.S. Pat. No. 5,382,573 issued Jan. 17, 1995, which relates to an HRT preparation and package. Casper is also the holder of U.S. Pat. No. 5,276,022 issued Jan. 4, 1994 and U.S. Pat. No. 5,585,370 issued Dec. 17, 1996 both of which relate to contraceptive therapy. The disclosures of all of these patents are incorporated herein by reference.
The Casper hormone replacement therapy (HRT) and hence the cyclophasic regimens disclosed by Casper seek to induce higher levels of progestogen and estrogen receptors by an estrogen-induced increase in receptor production. The greater concentration of steroid receptors increases the sensitivity of the target organs to progestogen and estrogen and allows the use of lower doses of exogenous steroids. The cyclophasic or interrupted regimens of Casper upregulate the estrogen and progestogen receptors in an estrogen-dominant phase and then down-regulate the same receptors in a progestogen-dominant phase. In both phases of the Casper regimen, the estrogen dose is constant while the progestogen dose is varied to produce relatively progestogen-dominant or estrogen-dominant effects. These alternating phases continue without interruption in the Casper HRT regimen.
Hot flashes or flushes occur in about 75 percent of menopausal women. The flushes may begin in the perimenopausal period when relative estrogen deficiency occurs together with cycle irregularity secondary to anovulation, but they usually begin during or after the menopause. Hot flushes typically begin as a sudden sensation of heat centered on the face and upper chest that rapidly becomes generalized. The sensation of heat lasts between two and four minutes, is frequently associated with profuse perspiration and occasionally palpitations, and is often followed by chills and shivering [Casper, R F,. Yen, S S C. Neuroendocrinology of menopausal flushes: An hypothesis of flush mechanism. Clin Endocrinol 1985; 22:293].
Hot flushes usually occur several times per day, although the range may be from only one or two each day to as many as one per hour during the day and night. Flushes cause arousal from sleep, leading to sleep disturbances. In addition, many women have profuse perspiration, which can be embarrassing in social situations.
The cause of hot flushes is unknown. They are thought to be due to thermoregulatory dysfunction, initiated at the level of the hypothalamus by estrogen withdrawal [ibid.] Evidence for central mediation of the changes in temperature comes from studies demonstrating that hot flushes occur simultaneously with pulses of luteinizing hormone [Casper, R F, Yen, S S C, Wilkes, M M. Menopausal flushes: A neuroendocrine link with pulsatile luteinizing hormone secretion. Science 1979; 205:823 and Tataryn, I V, 30 Meldrum, D R, Lu, K H, et al. LH, FSH and skin temperature during the menopausal hot flash. J Clin Endocrinol Metab 1979; 49:152].
A speculative mechanism for the initiation of hot flushes is endogenous opioid peptide withdrawal. Estrogen increases central opioid peptide activity, while menopause appears to be associated with decreased or absent endogenous central opioid activity [Reid, R L, Quigley, M E, Yen, S S. The disappearance of opiodidergic regulation of gonadotropin secretion in postmenopausal women. J Clin Endocrinol Metab 1983; 573107].
Whatever the cause of hot flushes, the most effective way known to prevent or treat them in women with estrogen deficiency is to administer estrogen.
In women who have not had a hysterectomy, estrogen should always be given in combination with a progestogen, to prevent the occurrence of endometrial hyperplasia and associated malignancies of the endometrium. Estrogen-progestogen therapy also is more effective than estrogen alone in ameliorating hot flushes, possibly because progestogen also increases central opioid peptide activity [Casper, R F, Alapin-Rubillowicz, S J. Progestogen 15 increases endogenous opioid peptide activity in postmenopausal women. J Clin Endocrinol Metab 1985; 60:34].
Progestogen administration alone can inhibit gonadotropin secretion, increase hypothalamic endogenous opioid peptide activity [Casper, R F, Alapin Rubillowicz, S J. Progestogen increases endogenous opioid peptide activity in postmenopausal women. J Clin Endocrinol Metab 1985; 60:34], and ameliorate hot flashes Schiff, I. The effects of progestogen on vasomotor flushes. J Rep rod Med 1982; 27(Suppl):498]. As an example, megestrol acetate (at a dose of 20 to 80 mg/day) decreases the frequency of hot flushes by 85 percent (versus 21 percent with placebo) [Loprinrzi, C L, Michalak,. J C, Quella, S K, et al. Megestrol 25 acetate for the prevention of hot flashes. N Engl J Med 1994; 331:347]. Other progestogens such as norethindrone acetate (10 mg daily) are also effective.
The bothersome symptoms of hot flushes are the most frequent reason for women to seek hormone replacement therapy. The improvement in hot flushes leads to long term utilization of hormone replacement therapy with many additional benefits of such use including a 50% reduction in heart disease, prevention of osteoporosis, and perhaps, as new evidence indicates, prevention of Alzheimer's disease. At the present time, the major controversial area concerning the risks of hormone replacement therapy involves breast cancer. It is believed, but not proven, that the risk of breast cancer in women taking hormone replacement therapy is related to the dose of estrogen exposure over time.
Despite substantial efforts made to date, there remains a need for improved HRT regimens that minimize estrogen exposure, while effectively relieving symptoms such as hot flushes.